Cisplatin, a cancer chemotherapy drug first approved by the FDA in 1978, revolutionized the treatment of many types of cancer.  Despite its effectiveness, in many cases doctors are forced to reduce the drug’s dose, or abandon it altogether, due to serious side effects on patients’ hearing.

Between 10-25% of adults and up to 60% of children being treated with cisplatin suffer from severe, permanent hearing loss in both ears. This is particularly damaging in kids, because even mild hearing loss can negatively impact learning and social development.

Researchers have suggested that genetic variants that affect the metabolism of cisplatin might explain why some people are susceptible to drug-induced hearing loss, while other patients receiving similar doses are not.  A new report, published online this week in the journal Nature Genetics, has identified variants in two genes that appear to greatly increase the risk of cisplatin-induced hearing loss.  Although the study is a small one, if replicated these findings could one day help doctors make better decisions about how to prescribe cipslatin.

A team led by Colin Ross from the University of British Columbia analyzed the DNA of 162 children (mostly of European ancestry) treated with cisplatin, focusing their search for genetic variants associated with drug-induced hearing loss on 220 genes known to be involved in the absorption, distribution, metabolism and elimination of medications and their breakdown products.

The variants with the largest effects were found in the TPMT gene.  For example, having one or two Cs at rs1142345 increased the odds of cisplatin-induced hearing loss by 10.51 times, although this result was not statistically significant once the researchers adjusted their data to account for the number of SNPs investigated.

(A larger and statistically significant effect was seen with closely related TPMT SNP, rs12201199, that 23andMe does not currently provide data for.  23andMe customers can use the links in this post to check their data using the Browse Raw Data feature.)

Rs1142345, as well as other variants that reduce the function of the TPMT enzyme, have been associated with adverse reactions to a class of drugs called thiopurines that are used as chemotherapy agents and immune system suppressants.

A second SNP associated with cisplatin-induced hearing was rs9332377 in the COMT gene.  Having one or two Ts at this SNP increased the odds of hearing loss by 5.52 times.  This result was also not statistically significant after adjusting the data.

Other variations in the COMT gene have been associated with a variety of traits, including pain sensitivity, willingness to explore new options, recovery from heart surgery, anxiety, and decreased breast cancer risk in tea drinkers.

None of the SNPs identified in this study were associated with hearing loss in children not treated with cisplatin, suggesting that their effect is specific for drug-induced hearing loss.

“These findings suggest that it may be possible identify individuals at higher risk of cisplatin otoxicity [hearing loss] based on genotype, which would improve counseling and treatment options,” the authors write.

They suggest, for example, that children with the riskier versions of the variants identified in this study could be given lower doses of cisplatin or treated instead with carboplatin, a drug that shows nearly similar cancer cure rates as cisplatin, but has less tendency to cause hearing damage.

The authors acknowledge, however, that their results will need to be replicated in independent populations before any decisions about how to use information about these variants in clinical settings can be made.  Research is also needed to understand what, if any, role these variants play in cisplatin-induced hearing loss in adult cancer patients.

Note: Recent studies by other researchers showed that variations in the megalin gene, the GSTP1 gene and the GSTM1 gene were also associated with the risk of cisplatin-induced hearing loss.  The current report from Ross et al. failed to replicate these associations.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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New research suggests that a gene associated with breast cancer can influence a woman’s chances of surviving the disease, particularly if she receives a drug treatment commonly given after surgery, according to a study published online Friday in Nature Genetics.

Fagerholm et al studied the gene NQO1 in 1,005 breast cancer patients from Finland and found that a woman’s survival was associated with her genotype at a particular SNP in the gene – rs1800566. After 5 years, about 85% of patients with one or two copies of G at rs1800566 survived, whereas only 65% of those with two A versions (AA genotype) did. The researchers saw similar results were seen in a second set of 1,162 Finnish female breast cancer patients – 72% of GG and GA genotype patients survived after 10 years, while only 46% of AA genotype patients did.

These results could impact a large number of women – according to the study 4% of people of European descent and up to 20% of the Asian population have the AA genotype at rs1800566.

Epirubicin is part of a drug cocktail that is often given as a chemotherapy treatment after removal of a breast tumor. When Fagerholm et al studied a subset of patients who received the treatment, they found that those with the AA version of rs1800566 were much less likely to survive.

The survival rate for women with the GG or GA genotype at rs1800566 who received epirubicin-based chemotherapy was 75% after 5 years. But for those women receiving epirubicin who had the AA genotype at this SNP, the survival rate was only 17%. There was no statistical difference in this study in survival rate for women who received other types of treatment or no treatment at all, regardless of their genotype.

The A version of rs1800566 causes a change in the protein sequence of NQO1 that results in the protein being destroyed by cells. Having the AA genotype at rs1800566 leaves cells completely devoid of NQO1 protein. Laboratory tests found that cells with the AA genotype, as well as cells engineered to lack the NQO1 protein (mimicking the AA genotype), were not as efficiently killed by epirubicin as cells that do contain the protein. The study showed that the effectiveness of other types of cancer treatment, including radiation and other drugs, were not affected by rs1800566 genotype or the amount of NQO1 present.

Approximately 20% of breast cancer tumors have a mutated version of an important tumor suppressor protein called p53. When the researchers analyzed the original group of 1,005 patients according to whether or not their tumors had this mutation (p53 information wasn’t available for the second study group), the AA genotype at rs1800566 had an effect only in women whose tumors had mutated p53. Only 20% of these women survived 5 years, whereas 73% of women with the GG or GA genotype and mutated p53 survived. In women with normal p53 protein, rs1800566 did not affect survival.

Based on the clinical and experimental results in their report – and the fact that the NQO1 protein is known to interact with the p53 protein – the authors speculate that NQO1 and p53 not only work together to prevent cancer but are both needed for drugs like epirubicin to destroy cancer cells that do develop.

The researchers theorize that in cells with functional copies of both the p53 and NQO1 genes, epirubicin treatment causes cell death. In cells that are deficient in either one of these proteins the effects of epirubicin may be less pronounced, but the end result is still the desired cancer cell death. But in cells that lack functional copies of both p53 and NQO1, the researchers think that signaling pathways are disturbed in such a way that epirubicin treatment not only is ineffective at killing cancer cells, but it may even enhance cancer cell survival and/or promote progression and spread of the disease.

The authors say that although more studies will be needed to confirm their findings, “NQO1 genotype may provide a predictive factor for treatment, possibly in combination with p53 status, both for primary tumors and, crucially, in metastatic breast cancer, where response to chemotherapy is critical for the treatment outcome and life expectancy.”

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